Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Dengue virus (DENV) infection requires cholesterol as a pro-viral factor although statin treatment did not show antiviral efficacy in dengue patients. Here, we show that DENV infection manipulates cholesterol metabolism in cells residing in low oxygen microenvironments (hypoxia) such as the liver, spleen and lymph nodes. DENV infection induced proprotein convertase subtilisin/kexin type 9 (PCSK9), which reduces low-density lipoprotein receptor (LDLR) recycling and hence cholesterol uptake. We found that, whereas LDLR uptake would have distributed cholesterol throughout the various cell compartments, de novo cholesterol synthesis enriched this lipid in the endoplasmic reticulum (ER). With cholesterol enrichment in the ER, ER-resident STING and type-I interferon (IFN) activation were repressed during DENV infection. Our in vitro findings were further supported by the finding of elevated plasma PCSK9 levels in dengue patients with high viremia and increased severity of plasma leakage. Our findings thus suggest PCSK9 plays a hitherto unrecognized role in dengue pathogenesis and therefore PCSK9 inhibitors could be a suitable host-directed treatment for dengue patients.

Original publication

DOI

10.1172/JCI137536

Type

Journal article

Journal

J Clin Invest

Publication Date

09/07/2020

Keywords

Infectious disease, hypoxia